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Aging Cell. 2013 Jun;12(3):370-80. doi: 10.1111/acel.12057. Epub 2013 Mar 24.

mTOR regulates tau phosphorylation and

degradation: implications for Alzheimer's disease
and other tauopathies
Antonella Caccamo 1 , Andrea Magrì, David X Medina, Elena V Wisely, Manuel F López-Aranda,
Alcino J Silva, Salvatore Oddo

Affiliations
PMID: 23425014 PMCID: PMC3655115 DOI: 10.1111/acel.12057
Free PMC article

Abstract
Accumulation of tau is a critical event in several neurodegenerative disorders, collectively known as
tauopathies, which include Alzheimer's disease and frontotemporal dementia. Pathological tau is
hyperphosphorylated and aggregates to form neurofibrillary tangles. The molecular mechanisms
leading to tau accumulation remain unclear and more needs to be done to elucidate them. Age is a
major risk factor for all tauopathies, suggesting that molecular changes contributing to the aging
process may facilitate tau accumulation and represent common mechanisms across different
tauopathies. Here, we use multiple animal models and complementary genetic and pharmacological
approaches to show that the mammalian target of rapamycin (mTOR) regulates tau phosphorylation
and degradation. Specifically, we show that genetically increasing mTOR activity elevates
endogenous mouse tau levels and phosphorylation. Complementary to it, we further demonstrate
that pharmacologically reducing mTOR signaling with rapamycin ameliorates tau pathology and the
associated behavioral deficits in a mouse model overexpressing mutant human tau. Mechanistically,
we provide compelling evidence that the association between mTOR and tau is linked to GSK3β and
autophagy function. In summary, we show that increasing mTOR signaling facilitates tau pathology,
while reducing mTOR signaling ameliorates tau pathology. Given the overwhelming evidence that
reducing mTOR signaling increases lifespan and healthspan, the data presented here have
profound clinical implications for aging and tauopathies and provide the molecular basis for how
aging may contribute to tau pathology. Additionally, these results provide preclinical data indicating
that reducing mTOR signaling may be a valid therapeutic approach for tauopathies.

© 2013 John Wiley & Sons Ltd and the Anatomical Society.

Figures
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 Figure 1. mTOR Figure 2. Autophagy Figure 3. Rapamycin
signaling inversely induction is decreased improves motor
correlates with… in… deficits in…

Figure 4. Rapamycin Figure 5. mTOR Figure 6. Autophagy

decreases tau signaling is decreased induction is increased
pathology in… in… in…

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